pharmaceuticals Review Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection Isabella Zanella 1,2,* , Daniela Zizioli 1, Francesco Castelli 3 and Eugenia Quiros-Roldan 3 1 Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; [email protected] 2 Clinical Chemistry Laboratory, Cytogenetics and Molecular Genetics Section, Diagnostic Department, ASST Spedali Civili di Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy 3 University Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili di Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy; [email protected] (F.C.); [email protected] (E.Q.-R.) * Correspondence: [email protected]; Tel.: +39-030-399-6806 Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is spreading worldwide with different clinical manifestations. Age and comorbidities may explain severity in critical cases and people living with human immunodeficiency virus (HIV) might be at particularly high risk for severe progression. Nonetheless, current data, although sometimes contradictory, do not confirm higher morbidity, risk of more severe COVID-19 or higher mortality in HIV-infected people with complete access to antiretroviral therapy (ART). A possible protective role of ART has been hypothesized to explain these observations. Anti-viral drugs used to treat HIV infection have been repurposed for COVID-19 treatment; this is also based on previous studies on severe acute respiratory syndrome virus (SARS-CoV) and Middle East respiratory syndrome virus (MERS-CoV). Among Citation: Zanella, I.; Zizioli, D.; them, lopinavir/ritonavir, an inhibitor of viral protease, was extensively used early in the pandemic Castelli, F.; Quiros-Roldan, E. but it was soon abandoned due to lack of effectiveness in clinical trials. However, remdesivir, a Tenofovir, Another Inexpensive, nucleotide analog that acts as RNA-dependent RNA-polymerase inhibitor, which was tested early Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 during the pandemic because of its wide range of antiviral activity against several RNA viruses Infection. Pharmaceuticals 2021, 14, 454. and its safety profile, is currently the only antiviral medication approved for COVID-19. Tenofovir, https://doi.org/10.3390/ph14050454 another nucleotide analog used extensively for HIV treatment and pre-exposure prophylaxis (PrEP), has also been hypothesized as effective in COVID-19. No data on tenofovir’s efficacy in coronavirus Academic Editors: Jean Jacques infections other than COVID-19 are currently available, although information relating to SARS-CoV-2 Vanden Eynde and Annie Mayence infection is starting to come out. Here, we review the currently available evidence on tenofovir’s efficacy against SARS-CoV-2. Received: 12 April 2021 Accepted: 5 May 2021 Keywords: tenofovir; nucleoside/nucleotide analogues; RNA-dependent RNA polymerase inhibitors; Published: 11 May 2021 nucleotide SARS-CoV-2; COVID-19 treatment Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. COVID-19 (coronavirus disease 2019), caused by the severe acute respiratory syn- drome virus 2 (SARS-CoV-2), has been defined as a pandemic around the world by the World Health Organization (WHO). Millions of people are currently infected and the dis- ease causes death in 5–10% of patients. COVID-19 was first reported in December 2019, Copyright: © 2021 by the authors. and at that time we faced a disease without available drugs for treatment or prevention. Licensee MDPI, Basel, Switzerland. Antiviral therapies are a key medical countermeasure for emerging viral infections because This article is an open access article vaccine production takes a long time whereas effective antiviral medications may already distributed under the terms and exist. Further, even though several vaccines have been proven effective in providing pro- conditions of the Creative Commons Attribution (CC BY) license (https:// tection against COVID-19 or at least in preventing serious illness and death and they have creativecommons.org/licenses/by/ been fully approved for use in humans by the appropriate authorities in many parts of 4.0/). Pharmaceuticals 2021, 14, 454. https://doi.org/10.3390/ph14050454 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, 454 2 of 16 the world [1–3], it is unknown whether they can provide long-term protection, are com- pletely or only partly efficacious against the new emerging virus variants and will soon be available in low-resource settings around the world. Therefore, also considering that some patients cannot be vaccinated because of health conditions, there is still an urgent need for efficacious and easily accessible therapies against the pandemic disease. For COVID-19, the potential of several existing medications (including remdesivir, lopinavir/ritonavir, hydroxychloroquine and tocilizumab) have been of interest based on previous studies of well-known coronavirus family members: severe acute respiratory syndrome virus (SARS- CoV) and Middle East respiratory syndrome virus (MERS-CoV). One approach to treat viral infection is targeting viral functional proteins [4]. Like SARS-CoV and MERS-CoV, SARS-CoV-2 is an enveloped positive-sense single-stranded RNA virus. Viral particles consist of structural proteins that surround and interact with the viral genome, namely, the spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins. The virus infects target cells after specific binding of the receptor-binding domain (RBD) of the viral protein S to the cellular entry receptor, the angiotensin-converting enzyme 2 (ACE2). Following entry, virions are uncoated, viral RNA is released and immediately translated into two large polyproteins (pp1a and pp1a), specified by two large open reading frames of the viral RNA (ORF1a and ORF1b). These polyproteins are then cleaved by two viral proteases, the papain-like protease (PLpro) and the main protease or 3C-like protease (Mpro/3CLpro), releasing 16 non-structural proteins (nsp1–16). Most of these proteins are involved in the intracellular replication cycle of SARS-CoV-2, in particular, nsp12 is the RNA dependent RNA polymerase (RdRp) that with the cofactors nsp7 and nsp8 performs viral RNA synthe- sis for translation and synthesis of structural and accessory proteins and for the assembly of new virions [4–6] (Figure1). SARS-CoV-2 shares 82% RNA sequence identity with SARS-CoV and MERS-CoV, therefore, at the beginning of the pandemic, known drugs targeting viral RdRp of SARS- CoV or other coronaviruses were repurposed due to the urgent need for an antiviral therapy for the new member of the family, SARS-CoV-2. Among them, remdesivir (an adenosine analog) was tested early during the pandemic because of its wide range of antiviral activity against several RNA viruses (including Ebola virus, SARS-CoV and MERS-CoV) and its safety profile. Currently, it is the only antiviral medication approved for COVID-19 [7]. Early during the COVID-19 pandemic, lopinavir/ritonavir, an old drug used for human immunodeficiency virus (HIV) treatment, was also extensively used as a potential therapy against the new virus [8]. Lopinavir is a type 1 aspartate protease inhibitor with in vitro and in vivo activity against SARS-CoV and in an animal model against MERS-CoV [9]; however, after the first wave of COVID-19 it was soon abandoned due to its lack of effectiveness in clinical trials [10–12]. Generally, immunocompromised patients are more susceptible to bacterial, fungal, viral, and parasitic infections than healthy persons due to their inability to mount successful immune responses. For these reasons, at the beginning of pandemic, HIV-infected patients, who constitute 0.5% of the world population [13] were considered as high risk for severe COVID-19 [14,15], and if their antiviral therapy could be shifted to lopinavir without decreasing efficacy against HIV infection, it was done during the first wave [8,15–17]. Today, lopinavir is no longer used for COVID-19 treatment outside of clinical trials [18]. Up until now, it is not clear whether HIV infection increases COVID-19 risk in settings with complete access to antiretroviral drugs (ARVs) against HIV [19–23]. The concern over increased risk for severe COVID-19 disease for HIV-infected patients may be based on the assumption that these subjects are more likely to be immunosuppressed because HIV infection is associated with abnormal humoral and T-cell–mediated immune responses, resulting in increased susceptibility to numerous opportunistic infections. There may also be a higher prevalence of co-morbidities that appear to be driving factors for COVID-19 mortality such as hypertension, diabetes, chronic lung disease, serious cardiovascular conditions, chronic kidney disease, or chronic liver disease or cancer [24,25]. Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 17 thorities in many parts of the world [1–3], it is unknown whether they can provide long-term protection, are completely or only partly efficacious against the new emerging virus variants and will soon be available in low-resource settings around the world. Therefore, also considering that some patients cannot be vaccinated because of health conditions, there is still an urgent need for efficacious and easily accessible therapies against the pandemic disease.